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Chapter Ten 10 Physiology David Williams, Anna Kenyon & Dawn Adamson CHAPTER CONTENTS Biophysical definitions 174 Molecular weight 174 Respiration 193 The lungs, ventilation and its control 193 Distribution of water and electrolytes 174 Oxygen and carbon dioxide transport 197 Transport mechanisms 175 Urinary system 199 Acid–base balance 177 Microanatomy 199 Normal acid–base balance 177 Renal clearance 200 Abnormalities of acid–base balance 180 Glomerular filtration rate 200 Cardiovascular system 181 Renal blood flow 201 Conduction system of the heart 181 Handling of individual substances 201 Factors affecting heart rate 181 Endocrine functions of the kidney 202 Electrocardiogram (ECG) 181 Effects of pregnancy 203 Pressure and saturation in the cardiac chambers 183 Physiology of micturition 205 Haemodynamic events in the cardiac cycle and their clinical correlates 183 Control of cardiac output 184 Changes in blood volume and cardiac output during pregnancy 186 Blood pressure control 186 Blood pressure changes in pregnancy 188 Endothelium in pregnancy 188 Endothelium as a barrier 188 Endothelium as a modulator of vascular tone 189 Gastrointestinal tract 205 Mouth 205 Oesophagus 206 Gall bladder 208 Small intestine 208 Large intestine (caecum, colon, rectum and anal canal) 209 Liver 211 Anatomical considerations 211 Metabolic function 211 Testing liver function 214 Oestrogen and the endothelium 191 Miscellaneous functions 214 Endothelium and haemostasis 191 Nervous system 215 Endothelium and inflammation 192 Somatic nervous system 215 Pre-eclampsia 192 Reticular activating system 217 Conclusion 193 Autonomic nervous system 218 Biophysical definitions Blood 219 Iron metabolism 219 Haemopoiesis and iron metabolism in pregnancy 221 Haemostasis 223 Haemostasis and pregnancy 223 Measurements in medicine are wherever possible being made in Systeme Internationale (SI) units Under this system, the concentration of biological materials is expressed in the appropriate molar units (often mmol) per litre (L) The units used in the measurement of osmotic pres sure are considered below Rhesus incompatibility 228 Biophysical definitions Molecular weight One mole of an element or compound is the atomic weight or molecular weight, respectively, in grams For example, 1 mol of sodium is 23 g (atomic weight Na = 23) and 1 mol of sodium chloride is 58.5 g (atomic weight Cl = 35.5; 35.5 + 23 = 58.5) A ‘normal’ (molar) solution contains 1 mol/L of solution Therefore a ‘normal’ solution of sodium chloride contains 58.5 g and is a 5.85% solution This is very different from a physiological ‘normal’ solution of sodium chloride, where the concentration of sodium chloride (0.9%) is adjusted so that the sodium has the same concentration as the total number of cations in plasma (154 mmol/L) The concentrations of biological substances are usually much weaker than molar However, commonly used intravenous solutions that combine sodium chloride with glucose often contain sodium chloride 0.18% (sodium 30 mmol/L and chloride 30 mmol/L) and glucose 4% Injudicious use of excessive volumes of this combination with 30 mmol NaCl will quickly lead to hyponatraemia The conventional nomenclature for decreasing molar concentrations is given below The same prefixes may be used for different units of measurement: 1millimole ( mmol) = × 10 -3 mol 1micromole ( mmol) = × 10 -6 mol 1nanomole ( nmol) = × 10 -9 mol 1picomole ( pmol) = × 10 -12 mol femtomole ( fmol) = × 10 -15 mol attomole ( amol) = × 10 -18 mol 1 equivalent (Eq) = 1 mol divided by the valency Thus 1 Eq of sodium (valency 1) = 23 g, and 1 mol of sodium = 1 Eq, i.e 1 mmol = 1 mEq However, 1 Eq of calcium (valency 2, mol wt 40) = 20 g 1 mol of calcium = 2 Eq, and 1 mmol Ca2+ = 2 mEq Ca2+ 174 Distribution of water and electrolytes A normal 70 kg man is composed of 60% water, 18% protein, 15% fat and 7% minerals Obese individuals have relatively more fat and less water Of the 60% (42 L) of water, 28 L (40% of body weight) are intra cellular; the remaining 14 L of extracellular water are made up of 10.5 L of interstitial fluid (extracellular and extravascular) and 3.5 L of blood plasma The total blood volume (red cells and plasma) is 8% of total body weight, or about 5.6 L Total body water can be measured by giving a subject deuterium oxide (D2O), ‘heavy water’, and measuring how much it is diluted Extracellular fluid volume can be measured with inulin by the same prin ciple Intracellular fluid volume = total body water (D2O space) less extracellular fluid volume (inulin space) Intravascular fluid volume can be measured with Evans blue dye Total blood volume can be calcu lated knowing intravascular fluid volume and the haem atocrit Interstitial fluid volume = extracellular fluid volume (inulin space) less intravascular fluid volume The distribution of electrolytes and protein in intra cellular fluid, interstitial fluid and plasma is given in Figure 10.1 Note that, for reasons of comparability, concentrations are expressed in milliequivalents per litre (mEq/L) of water, not millimoles per litre (mmol/L) of plasma The major difference between plasma and inter stitial fluid is that interstitial fluid has relatively little protein As a consequence, the concentration of sodium in the interstitial fluid is less and so is the overall osmotic pressure (see below) There are further major differences between intracellular fluid and extracellular fluid Sodium is the major extracellular cation, whereas potassium and, to a lesser extent, magnesium are the predominant intracellular cations Chloride and bicar bonate are the major extracellular anions; protein and phosphate are the predominant intracellular anions Anion gap In considering the composition of plasma for clinical purposes, account is often taken of the ‘anion gap’ This is calculated by considering sodium the principal cation, 136 mEq/L, and subtracting from it the concentrations of the principal anions, chloride, 100 mEq/L, and CHAPTER 10 Physiology HCO3– 10 200 175 Extracellular fluid HCO3– 27 mEq/L H2O 150 HCO3– 27 125 100 Na+ 152 75 Na+ 143 Cl– 113 Cl– 117 50 Protein 74 Na+ 14 25 – PO4–– 113 K+ 157 K+ Ca+ Protein 16 K+ Ca++ Blood plasma Protein Interstitial fluid Mg++ 26 Cell fluid Figure 10.1 • Electrolyte composition of human body fluids bicarbonate, 24 mEq/L This leaves a positive balance of 12 mEq/L The normal range is 8–16 mEq/L The gap is considered to exist because of the occur rence of unmeasured anions, such as protein or lactate, which would balance the number of cations An increase in the anion gap suggests that there are more unmeasured anions present than usual This occurs in such situations as lactic acidosis, or diabetic ketoacido sis, where the lactate and acetoacetate are balancing the excess sodium ions A more complete explanation of the anion gap would be to consider both the unmeas ured cations as well as the unmeasured anions, as in Table 10.1 Situations where the anion gap is increased include ketoacidosis, lactic acidosis and hyperosmolar acidosis, and poisoning with salicylate, methanol, eth ylene glycol and paraldehyde, and hypoalbuminaemia A decreased anion gap occurs in bromide poisoning and myeloma Table 10.1 Anion gap (mEq/L) Cation + Na These mechanisms account for the movement of sub stances within cells and across cell membranes The transport mechanisms to be considered include diffusion, solvent drag, filtration, osmosis, non-ionic diffusion, carrier-mediated transport and phagocytosis Not all of these mechanisms will be considered in detail Diffusion is the process whereby a gas or substance in solution expands to fill the volume available to it 136 Cl− 100 HCO3− 24 —— —— 136 124 Gap 12 —— —— 136 136 The gap consists of unmeasured cations and anions: K+ Ca Transport mechanisms Anion 4.5 2+ Mg2+ Protein 15 PO4 3− 1.5 SO42− Organic acids —— —— 11 23 —— —— 147 147 175 Transport mechanisms Relevant examples of gaseous diffusion are the equili bration of gases within the alveoli of the lung, and of liquid diffusion, the equilibration of substances within the fluid of the renal tubule An element of diffusion may be involved in all transport across cell membranes because recent research suggests that there is a layer of unstirred water up to 400 µm thick adjacent to bio logical membranes in animals If there is a charged ion that cannot diffuse across a membrane which other charged ions can cross, the diffusible ions distribute themselves as in the following example: In K i+ Cli − Protein− Out K 0+ Cl0 − [ K i+ ] = [ Cl0 - ] [ K 0+ ] [ Cli- ] osmol = mol.wt in grams number of osmotically active particles s in solution So for an ideal solution of glucose: osmol = mol.wt = mol.wt = 180 g However, sodium chloride dissociates into two ions in solution Therefore, for sodium chloride: osmol = mol.wt = 58.5 = 29.2 g Calcium chloride dissociates into three ions in solution Therefore, for calcium chloride, Gibbs-Donnan equilibrium The cell is permeable to K+ and Cl− but not to protein Since Ki is about 157 mmol/L and K0 is 4 mmol/L, the Gibbs–Donnan equilibrium would predict that the ratio of chloride concentration outside the cell to that inside should be 157/4, i.e about 40 In fact, there is almost no intracellular chloride so that the ratio in vivo is even greater than 40 This is because there are other factors than simple diffusion affecting both potassium and chloride concentrations Solvent drag is the process whereby bulk movement of solvent drags some molecules of solute with it It is of little importance Filtration is the process whereby substances are forced through a membrane by hydrostatic pressure The degree to which substances pass through the mem brane depends on the size of the holes in the mem brane Small molecules pass through the holes, larger molecules not In the renal glomerulus the holes are large enough to allow all blood constituents to pass through the filtration membrane, apart from blood cells and the majority of plasma proteins Osmosis describes the movement of solvent from a region of low solute concentration, across a semiper meable membrane to one of high solute concentration The process can be opposed by hydrostatic pressure; the pressure that will stop osmosis occurring is the osmotic pressure of the solution This is given by the formula: P = nRT V where, P = osmotic pressure, n = number of osmotically active particles, R = gas constant, T = absolute tem perature, V = volume For an ideal solution of a non176 ionized substance, n/V equals the concentration of the solute In an ideal solution, 1 osmol of a substance is then defined such that: osmol = mol.wt = 111 = 37 g However, the molecules or ions of all solutions aggre gate to a certain degree so that interaction occurs between the ions or molecules, and they each not behave as osmotically independent particles and not form ideal solutions Freezing point depression by a solution is also caused by the number of osmotically active particles The greater the concentration of osmotically active particles, the greater the freezing point depression In an ideal solution, with no inter action, 1 mol of osmotically active particles per litre depresses the freezing point by 1.86°C Therefore, an aqueous solution which depresses the freezing point by 1.86°C is defined as containing 1 osmol/L One which depresses the freezing point by 1.86°C/1000, i.e 0.00186°C, contains 1 mosmol/L Plasma (osmotic pressure 300 mosmol/L) has a freezing point of (0 -0.00186 × 300)°C = –0.56°C Osmolarity defines osmotic pressure in terms of osmoles per litre of solution Since volume changes at different temperatures, osmolality which defines osmotic pressure in terms of osmoles per kilogram of solution is preferred, though not always employed The major osmotic components of plasma are the cations sodium and potassium, and their accompanying anions, together with glucose and urea The concentration of sodium is about 140 mmol/L This, and the accompanying anions, will therefore con tribute 280 mosmol/L The concentration of potassium is about 4 mmol/L, which, with its accompanying anions, will give 8 mosmol/L Glucose and urea con tribute 5 mosmol/L each to a total of 300 mosmol/L in normal plasma During pregnancy, due to an expan sion of plasma volume this falls to below 290 mosmol/L The mechanism of plasma volume expansion appears to relate to a resetting of the hypothalamic thirst Physiology centre, so that in early pregnancy women still feel thirsty at a lower plasma osmolality We are now in a position to consider some of the forces acting on water in the capillaries (Fig 10.2) The capillary membrane behaves as if it is only permeable to water and small solutes It is impermeable to colloids such as plasma protein There is a difference of 25 mmHg in osmotic pressure between the interstitial water and the intravascular water due to the intravascu lar plasma proteins (see above) This force (oncotic pressure) will tend to drive water into the capillary At the arteriolar end of the capillary, the hydrostatic pres sure is 37 mmHg; the interstitial pressure is 1 mmHg The net force driving water out is therefore 37 – – 25 = 11 mmHg, and water tends to pass out of the arteriolar end of the capillary At the venous end of the capillary, the pressure is only 17 mmHg The net force driving water in the capillary is therefore 25 + 1 – 17 = 9 mmHg Fluid therefore enters the capillary at the venous end Factors which would decrease fluid reabsorption and cause clinical oedema are a reduction in plasma proteins, so that the osmotic gradient between the intravascular and interstitial fluids might be only 20 mmHg, not 25 mmHg, or a rise in venous pressure so that the pressure at the venous end of the capillary might be 25 mmHg, rather than 17 mmHg Non-ionized diffusion is the process whereby there is preferential transport in a non-ionized form Cell membranes consist of a lipid bilayer with specific trans porter proteins embedded in it Lipid-soluble drugs, Arterial end 37—Hydrostatic pressure—17 11 25 36 25 Venous end 16 Interstitial hydrostatic pressure = 25 – 37 + = –11 25 – 17 + = Osmotic gradient Hydrostatic gradient All pressures are in mmHg Net effect Figure 10.2 • At the arterial end of the capillary the hydrostatic forces acting outwards are greater than the osmotic forces acting inwards There is a net movement out of the capillary At the venous end of the capillary, the hydrostatic forces acting outwards are less than the osmotic forces acting inwards There is a net movement into the capillary CHAPTER 10 e.g propranolol, can cross the lipids of the blood–brain barrier or the placenta by non-ionized diffusion But small hydrophilic molecules such as O2 can also diffuse across the lipid bilayer, which is also permeable to water Carrier-mediated transport implies transport across a cell membrane using a specific carrier If the transport is down a concentration gradient from an area of high concentration to one of low concentration, this is known as facilitated transport, e.g the uptake of glucose by the muscle cell, facilitated by the participa tion of insulin in the transport process If the carriermediated transport is up a concentration gradient from an area of low concentration to one of high concentra tion, this is known as active transport, e.g the removal of sodium from muscle cells by the ATPase-dependent sodium pump The channel may be ligand gated where binding of external (e.g insulin as earlier) ligands or an internal ligand opens the channel Alternatively the channel may be voltage gated, where patency depends on the transmembrane electrical potential; voltage gating is a major feature of the conduction of nervous impulses Phagocytosis and pinocytosis involve the incorpora tion of discrete bodies of solid and liquid substances, respectively, by cell wall growing out and around the particles so that the cell appears to swallow them If the cell eliminates substances, the process is known as exocytosis; if substances are transported into the cell, the process is endocytosis In endocytosis, the Golgi apparatus is involved in intracellular transport and processing to varying extents depending on whether exocytosis is via the non-constitutive pathway (exten sive processing) or the constitutive pathway (little processing) Similarly, endocytosis may involve specific receptors for substances such as low-density lipopro teins (receptor-mediated endocytosis) or there may be no specific receptors (constitutive endocytosis) Acid–base balance Normal acid–base balance A simple knowledge of chemistry allows some sub stances to be easily categorized as acids or bases For example, hydrochloric acid is clearly an acid and sodium hydroxide is a base But when describing acid– base balance in physiology, these terms are used rather more obscurely For example, the chloride ion may be described as a base A more applicable definition is to define an acid as an ion or molecule which can liberate hydrogen ions Since hydrogen ions are protons (H+), acids may also be defined as proton donors A base is then a substance which can accept hydrogen ions, or a proton acceptor If we consider the examples below, 177 Acid–base balance hydrochloric acid dissociates into hydrogen ions and chloride ions, and is therefore a proton donor (acid) If the chloride ion associates with hydrogen ions to form hydrochloric acid, the chloride ion is a proton acceptor (base) Ammonia is another proton acceptor when it forms the ammonium ion Carbonic acid is an acid (hydrogen ion donor); bicarbonate is a base (hydrogen ion acceptor) The H2PO4− ion can be both an acid when it dissociates further to HPO42− and a base when it associates to form H3PO4: HCl NH3 + H− H2 CO3 H3PO4 H2PO4 − H+ + Cl− NH4 + H+ + HCO3 − H2PO4 − + H+ H3PO4 − + H+ pH The pH is defined as the negative log10 of the hydrogen ion concentration expressed in mol/L A negative loga rithmic scale is used because the numbers are all less than 1, and vary over a wide range Since the pH is the negative logarithm of the hydrogen ion concentration, low pH numbers, e.g pH 6.2, indicate relatively high hydrogen ion concentrations, i.e an acidic solution High pH numbers, e.g pH 7.8, represent lower hydro gen ion concentrations, i.e alkaline solutions Because the pH scale is logarithmic to the base 10, a 1-unit change in pH represents a 10-fold change in hydrogen ion concentration The normal pH range in human tissues is 7.36–7.44 Although a neutral pH (hydrogen ion concentration equals hydroxyl ion concentration) at 20°C has the value 7.4, water dissociates more at physiological tempera tures, and a neutral pH at 37°C has the value 6.8 There fore, body fluids are mildly alkaline (the higher the pH number, the lower the hydrogen ion concentration) A pH value of 7.4 represents a hydrogen ion con centration of 0.00004 mmol/L as seen in the following example: pH [ H+ ] = 7.4 = 10 -7.4 mol L = 10 -8 × 10 0.6 mol L = 0.00000001 × mol L = 0.00000004 mol L = 0.00004 mmol L (1mol L = 1000 mmol L ) Partial pressure of carbon dioxide (Pco2) In arterial blood, the normal value is 4.8–5.9 kPa (36– 44 mmHg) It is a fortunate coincidence that the figures expressing Pco2 in mmHg are similar to those expressing the normal range for pH (7.36–7.44) 178 Henderson–Hasselbalch equation This equation describes the relationship of hydrogen ion, bicarbonate and carbonic acid concentrations (see Equation (3) below) It can be rewritten in terms of pH, bicarbonate and carbonic acid concentrations, as in Equation (4), but carbonic acid concentrations are not usually measured However, because of the presence of carbonic anhydrase in red cells, carbonic acid con centration is proportional to Pco2 (Equation (1)) Equation (4) can therefore be rewritten in terms of pH, bicarbonate and Pco2 (Equation (5)) All these data are usually available from blood gas analyses If we know any two of these variables, the third can be calculated Carbonic anhydrase: CO2 + H2O [ H2 CO3 ] (1) H2CO3 (2) H+ + HCO - By the Law of Mass Action: [ H2 CO3 ] = K [ H+ ] [ HCO3 - ] \ [H+ ] = (2) [H2 CO - ] K [HCO - ] (3) By taking logarithms of the reciprocal: − [HCO ] pH = K ′ + log [H2 CO ] K′ is a constant equal to 6.1: - [HCO3 ] pH = 6.1+ log [H2 CO3 ] [HCO ] pH = 6.1+ log Pa CO2 × 0.04 (4) (5)* Control of pH The Henderson–Hasselbalch equation, expressed in Equation (5), indicates that the variables controlling pH are Pco2 and bicarbonate concentration Ulti mately, Pco2 is controlled by respiration Short-term changes of pH may therefore be compensated for by changing the depth of respiration Bicarbonate concen tration can be altered by the kidneys, and this is the mechanism involved in the long-term control of pH Further details of these mechanisms are given on pp 197 and 201 *For Equation (5), because of the action of carbonic anhydrase, [H2CO3] is proportional to Paco2 For the given constants of equation (5), Pco2 is expressed in mmHg Physiology Buffers nate rather poor as a buffer for body fluids, since the pK is considerably towards the acidic side of the phys iological pH range (7.36–7.44) The buffer value of a buffer (mmol of hydrogen ion per gram per pH unit) is the quantity of hydrogen ions which can be added to a buffer solution to change its pH by 1.0 pH unit from pK + 0.5 to pK − 0.5 In blood, the most important buffers are proteins These are able to absorb hydrogen ions onto free car boxyl radicals, as illustrated in Figure 10.4 Of the pro teins available, haemoglobin is more important than plasma protein, partly because its buffer value is greater than that of plasma protein (0.18 mmol of hydrogen per gram of haemoglobin per pH unit, vs 0.11 mmol of hydrogen per gram of plasma protein per pH unit), but also because there is more haemoglobin than plasma protein (15 g haemoglobin per 100 mL vs 3.8 g of plasma protein per 100 mL) These two factors mean that haemoglobin has six times the buffering capacity of plasma protein In addition, deoxygenated haemoglobin is a weaker acid and a more efficient buffer than oxygen ated haemoglobin This increases the buffering capacity of haemoglobin where it is needed more, after oxygen has been liberated in the peripheral tissues 0% 100% 50% 50% Figure 10.3 • Effect of adding H+ (as HCl) to an HCO3− solution (as NaHCO3) The pH changes from 9.0 when the solution is 100% HCO3− and 0% H2CO3 to 7.44) In addition, we consider respira tory acidosis and alkalosis where the primary abnormal ity is in respiration (carbon dioxide control) and metabolic acidosis and alkalosis, which are best defined as abnormalities that are not respiratory in origin Only initial, single abnormalities will be considered For these single uncomplicated abnormalities, respiratory and metabolic acidosis and alkalosis can be defined according to Table 10.2, which gives the values of pH and Pco2 characterizing each abnormality Respiratory acidosis There is a low pH and a high Pco2 Here the basic abnormality is a failure of carbon dioxide excretion Table 10.2 Values of pH and Pco2 characterizing acidosis and alkalosis pH P co2 (kPa) P co2 (mmHg) Normal 7.36–7.44 4.8–5.9 36–44 Respiratory acidosis 5.9 >44 Respiratory alkalosis >7.44